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Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema.

Publication ,  Journal Article
Borel, F; Sun, H; Zieger, M; Cox, A; Cardozo, B; Li, W; Oliveira, G; Davis, A; Gruntman, A; Flotte, TR; Brodsky, MH; Hoffman, AM; Mueller, C ...
Published in: Proc Natl Acad Sci U S A
March 13, 2018

Chronic obstructive pulmonary disease affects 10% of the worldwide population, and the leading genetic cause is α-1 antitrypsin (AAT) deficiency. Due to the complexity of the murine locus, which includes up to six Serpina1 paralogs, no genetic animal model of the disease has been successfully generated until now. Here we create a quintuple Serpina1a-e knockout using CRISPR/Cas9-mediated genome editing. The phenotype recapitulates the human disease phenotype, i.e., absence of hepatic and circulating AAT translates functionally to a reduced capacity to inhibit neutrophil elastase. With age, Serpina1 null mice develop emphysema spontaneously, which can be induced in younger mice by a lipopolysaccharide challenge. This mouse models not only AAT deficiency but also emphysema and is a relevant genetic model and not one based on developmental impairment of alveolarization or elastase administration. We anticipate that this unique model will be highly relevant not only to the preclinical development of therapeutics for AAT deficiency, but also to emphysema and smoking research.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 13, 2018

Volume

115

Issue

11

Start / End Page

2788 / 2793

Location

United States

Related Subject Headings

  • alpha 1-Antitrypsin
  • Pulmonary Emphysema
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lung
  • Liver
  • Humans
  • Female
 

Citation

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Borel, F., Sun, H., Zieger, M., Cox, A., Cardozo, B., Li, W., … Mueller, C. (2018). Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Proc Natl Acad Sci U S A, 115(11), 2788–2793. https://doi.org/10.1073/pnas.1713689115
Borel, Florie, Huaming Sun, Marina Zieger, Andrew Cox, Brynn Cardozo, Weiying Li, Gabriella Oliveira, et al. “Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema.Proc Natl Acad Sci U S A 115, no. 11 (March 13, 2018): 2788–93. https://doi.org/10.1073/pnas.1713689115.
Borel F, Sun H, Zieger M, Cox A, Cardozo B, Li W, et al. Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2788–93.
Borel, Florie, et al. “Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema.Proc Natl Acad Sci U S A, vol. 115, no. 11, Mar. 2018, pp. 2788–93. Pubmed, doi:10.1073/pnas.1713689115.
Borel F, Sun H, Zieger M, Cox A, Cardozo B, Li W, Oliveira G, Davis A, Gruntman A, Flotte TR, Brodsky MH, Hoffman AM, Elmallah MK, Mueller C. Editing out five Serpina1 paralogs to create a mouse model of genetic emphysema. Proc Natl Acad Sci U S A. 2018 Mar 13;115(11):2788–2793.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 13, 2018

Volume

115

Issue

11

Start / End Page

2788 / 2793

Location

United States

Related Subject Headings

  • alpha 1-Antitrypsin
  • Pulmonary Emphysema
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Male
  • Lung
  • Liver
  • Humans
  • Female